In Vivo Pharmacologic Profile of YM158, a New Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors.

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 . . .) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are 'non-prostanoid' (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.

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“…Finally, YM‐158 has similar high affinity for TP and cys‐LT receptors in guinea pig trachea (Arakida et al. , 1998) (see later).…”

Section: Tp Receptor Antagonistsmentioning

confidence: 94%

Prostanoid receptor antagonists: development strategies and therapeutic applications

Jones

Giembycz

Woodward³

2009

British J Pharmacology

144

162

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“…Another example of bifunctional anti-inflammatory compounds is drugs behaving as thromboxane receptor antagonists and cysteinyl-leukotriene antagonists in the same molecule [82]. However, both of these classes of drug have, to date, only shown limited efficacy, at least in the treatment of allergic airway disease.…”

Section: Bifunctional Anti-inflammatory Drugsmentioning

confidence: 99%

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Page

Cazzola

2014

Eur Respir J

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Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting b 2 -agonist and an inhaled corticosteroid, and combinations of long-acting b 2 -agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of ''triple-inhaler'' fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called ''bifunctional drugs''. In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/antiinflammatory drugs and bifunctional anti-inflammatory drugs. @ERSpublications Bifunctional drugs offer an exciting new approach to the treatment of asthma and COPD

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“…For example, (2-(N-(4-(4-chlorobenzenesulfonylamino)butyl)-N-(3-(4-isopropylthiazol-2-yl)methoxy)benzyl)sulfamoyl)benzoic acid (KP-496) (Mizutani et al, 2008;Ishimura et al, 2009) and YM-158 (Fig. 11) (Arakida et al, 1998) are dual TP/cysteinyl leukotriene antagonists.…”

mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

395

414

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In Vivo Pharmacologic Profile of YM158, a New Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors.

Cited by 12 publications

References 31 publications

Prostanoid receptor antagonists: development strategies and therapeutic applications

Prostanoid receptor antagonists: development strategies and therapeutic applications

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

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